CN105218621A - One class dehydroabietic acid Benzimidazole Schiff base class Hete rocyclic derivatives with anti-tumor activity and its preparation method and application - Google Patents

Abstract

The invention discloses a class of dehydroabietic acid benzimidazole Schiff base derivatives with antitumor activity, a preparation method and application thereof. A dehydroabietic acid benzimidazole Schiff base heterocyclic derivative having a structure shown in general formula I of the present invention and a pharmaceutically acceptable salt thereof: in, A class of dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives involved in the present invention and pharmaceutically acceptable salts thereof have significant antitumor activity, and pharmacological experiments show that the dehydroabietic acid matrices of the present invention The derivatives of phosphine bases have significant inhibitory effects on human liver cancer cells HepG2 and SMMC-7721, which are equivalent to the positive control etoposide, and have the potential to develop anti-tumor drugs.

Description

A class of dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives with antitumor activity and its preparation method and application

technical field

The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives with antitumor activity, a preparation method and application thereof.

Background technique

According to statistics, 1.5 million people die from cancer every year in my country, ranking first in the cause of death. Tumor has become one of the major malignant diseases with the highest mortality rate in the world. The conventional method of tumor treatment is mainly chemotherapy, that is, cytotoxic agents such as DNA synthesis inhibitors or cell division inhibitors are used to inhibit tumor cells, but at the same time, these agents will also kill normal cells that proliferate rapidly, causing infection, Symptoms such as bleeding. Therefore, the development of tumor suppressor drugs with high selectivity, good safety and high efficacy is an important direction of modern tumor disease research.

Dehydroabietic acid is a natural diterpene resin acid separated from rosin, which contains about 5% in rosin, and more than 50% in disproportionated rosin, the main deep-processing product of rosin, and is a resource-rich Natural terpenoids. Dehydroabietic acid derivatives have a variety of biological activities, such as antibacterial, cytotoxic, antiulcer, antiviral, anti-inflammatory, immunosuppressive, antioxidative, etc., which have attracted the attention of researchers at home and abroad. In recent years, there have been many reports at home and abroad on the synthesis of derivatives with anti-tumor activity using dehydroabietic acid or analogues as the parent. These studies have shown that making full use of the biological activity, physiological activity, non-toxic and renewable natural characteristics of dehydroabietic acid, and carrying out structural modification and modification, it is hopeful to develop new anti-tumor drugs and improve the utilization value of rosin deep-processing products. Has a good development prospect.

Schiff base refers to a class of organic compounds that are formed from two functional groups of aldehyde (ketone) group and amine group to form imine group (-CH=N-) or methylimine group (-CR=N-). Schiff bases are a very important class of compounds, usually formed by the condensation of various active carbonyl compounds and amines, and their synthesis is relatively easy and diverse. Changing the substituent group on the carbonyl group, choosing flexible and diverse amines and changing the type and position of the donor atom can open up many different properties from chain to ring, from monodentate to multidentate, from symmetric to asymmetric. , Schiff base compounds with variable structures, which will have important chemical and biological significance.

Contents of the invention

In order to overcome the deficiencies in the above-mentioned prior art, the object of the present invention is to provide a class of dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives with high antitumor activity and a preparation method thereof and apply.

In order to achieve the above-mentioned technical purpose, the technical scheme adopted by the present invention is as follows: the present invention provides a dehydroabietic acid benzimidazole Schiff base heterocyclic derivative with the structure shown in general formula I and its pharmaceutically acceptable the salt:

in,

The preparation method of the dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives having the structure shown in general formula I of the present invention comprises the following steps:

(1) dehydroabietic acid obtains dehydroabietic acid methyl ester through acyl chloride, methyl esterification reaction, has the structure shown in general formula III:

(2) Methyl dehydroabietate is brominated by NBS to obtain methyl dehydroabietate 12-bromo, which has a structure shown in general formula IV:

(3) 12-bromodehydroabietic acid methyl ester is double-nitrated with fuming nitric acid to obtain 12-bromo-13,14-dinitrodeisopropyl dehydromethyl ester, which has the structure shown in general formula V:

(4) 12-bromo-13,14-dinitro deisopropyl dehydroabietic acid methyl ester is reduced by Fe/HCl to obtain 12-bromo-13,14-diamino deisopropyl dehydroabietic acid methyl ester, which has Structure shown in general formula VI:

(5) 12-bromo-13,14-diamino deisopropyl dehydroabietic acid methyl ester reacts with cyanogen bromide to prepare dehydroabietic acid imidazole derivatives, which have the structure shown in general formula VII:

(6) Dehydroabietic acid imidazole derivatives react with salicylaldehyde of different substituents to obtain dehydroabietic acid Schiff base derivatives of corresponding substituents, which have a structure shown in general formula I:

in,

The application of the dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives with the structure shown in formula I and the pharmaceutically acceptable salts thereof in the preparation of drugs for treating tumors.

Further, the tumor is liver cancer.

Beneficial effects: the present invention has antibacterial and antitumor activities, and pharmacological experiments show that the dehydroabietic acid Schiff base derivatives of the present invention have significant inhibitory effect on human liver cancer cells HepG2 and SMMC-7721.

The present invention introduces an imidazole heterocycle on the benzene ring of dehydroabietic acid, and generates the dehydroabietic acid benzimidazole Schiff base derivative by condensation of the amino group on the side chain of the imidazole heterocycle and the salicylaldehyde of different aryl substituents. things. The structures of such derivatives are relatively novel, and have not been reported at home and abroad. It has the value of developing antitumor drugs.

detailed description

The present invention is further illustrated by the following examples. It should be understood that these embodiments are illustrations and examples of the present invention, and do not limit the scope of the present invention in any way.

The present invention provides a dehydroabietic acid benzimidazole Schiff base heterocyclic derivative with a structure shown in general formula I and a pharmaceutically acceptable salt thereof:

in,

The preparation method of the dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives having the structure shown in general formula I of the present invention comprises the following steps:

(1) dehydroabietic acid obtains dehydroabietic acid methyl ester through acyl chloride, methyl esterification reaction, has the structure shown in general formula III:

(2) Methyl dehydroabietate is brominated by NBS to obtain methyl dehydroabietate 12-bromo, which has a structure shown in general formula IV:

(3) 12-bromodehydroabietic acid methyl ester is double-nitrated with fuming nitric acid to obtain 12-bromo-13,14-dinitrodeisopropyl dehydromethyl ester, which has the structure shown in general formula V:

(4) 12-bromo-13,14-dinitro deisopropyl dehydroabietic acid methyl ester is reduced by Fe/HCl to obtain 12-bromo-13,14-diamino deisopropyl dehydroabietic acid methyl ester, which has Structure shown in general formula VI:

(5) 12-bromo-13,14-diamino deisopropyl dehydroabietic acid methyl ester reacts with cyanogen bromide to prepare dehydroabietic acid imidazole derivatives, which have the structure shown in general formula VII:

(6) Dehydroabietic acid imidazole derivatives react with salicylaldehyde of different substituents to obtain dehydroabietic acid Schiff base derivatives of corresponding substituents, which have a structure shown in general formula I:

in,

The application of the dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives with the structure shown in formula I and the pharmaceutically acceptable salts thereof in the preparation of drugs for treating tumors.

The tumor is liver cancer.

Example 1

Synthesis of Methyl Dehydroabietate (III)

In a 500mL three-necked round-bottom flask, dissolve 30g (0.1mol) of dehydroabietic acid in 100mL of benzene, slowly add 10.9mL of thionyl chloride (0.15mol) and heat to reflux for 3h. After the reaction, remove the reaction solution under reduced pressure Benzene and excess thionyl chloride to obtain dehydroabietic acid chloride as yellow oil. Add 60mL of methanol into the bottle, heat to reflux for 3h, after the reaction, remove the solvent under reduced pressure, and recrystallize from ethanol to obtain white needle-like crystals which are methyl dehydroabietate (30.63g, 97.6%), m.p.62.3～63.9℃ .

Example 2

Synthesis of 12-bromodehydroabietic acid methyl ester (IV)

Dissolve 15g of methyl dehydroabietate in 100mL of dry acetonitrile, then add 12g of NBS to the mixed solution, and react in the dark for 24 hours at room temperature, evaporate the solvent acetonitrile under reduced pressure, and add 100mL of carbon tetrachloride while hot , after cooling, filter out the insolubles in the solution, evaporate the solvent carbon tetrachloride under reduced pressure, dissolve it with anhydrous methanol, and recrystallize to obtain 10.5 g of white needle-like crystals, which is 12-bromodehydroabietic acid methyl Ester, yield 67%, m.p.133.5～135.7℃.

Example 3

Synthesis of 12-Bromo-13,14-Dinitrodeisopropyldehydromethyl Ester (V)

Fully mix 19mL of fuming nitric acid and 1.5mL of concentrated sulfuric acid, and add 12-bromodehydroabietic acid methyl ester (3g) into the mixed acid of fuming nitric acid and concentrated sulfuric acid under the condition of ice bath, and stir the mixture for 40min , after the reaction, the mixture was poured into ice water (mainly ice), and a light yellow solid was precipitated in the ice water, and the light yellow solid was collected by filtration, separated and purified with a silica gel column, and the solvent was selected from petroleum ether acetone system (volume ratio 50:1), the pure compound 12-bromo-13,14-bisnitrodeisopropyldehydroabietic acid methyl ester (1 g, 30%) was obtained. m.p.173.6～175.2℃.

Example 4

Synthesis of 12-bromo-13,14-diaminodeisopropyldehydromethyl ester (VI)

Dissolve 0.22g of 12-bromo-13,14-bisnitrodeisopropyl dehydroabietic acid methyl ester in 20ml of absolute ethanol, add 1ml of distilled water, 0.3g of iron powder, and 8 drops of concentrated hydrochloric acid to the mixed solution , stirred and refluxed for 1.5 hours, after the reaction, filtered to remove unreacted iron powder, neutralized to neutral with sodium hydroxide, filtered, suction filtered to obtain a brownish-yellow liquid, and the solvent was removed under reduced pressure to obtain yellow oily 12-bromo - 13,14-Diaminodeisopropyldehydromethyl ester (0.18 g, 82%).

Example 5

Synthesis of Dehydroabietic Acid Imidazole Derivatives (VII)

Add 5 mL of water and 0.10 g of cyanogen bromide (1 mmol) into a solution of compound VI (0.18 g) in ethanol (20 mL), stir the mixture under reflux for 5 h, remove the solvent under reduced pressure, dissolve the residue with dichloromethane, and wash with water for 3 times, saturated sodium bicarbonate solution and saturated sodium chloride solution were washed once respectively, water was removed by anhydrous sodium sulfate, the solvent was removed under reduced pressure, the silica gel column was separated and purified, and the solvent was selected petroleum ether/acetone system (volume ratio 10:1), to obtain Compound VII (0.10 g, 45%).

Mp218-220°C; Anal. Calcd (%) for C ₁₉ H ₂₄ BrN ₃ O ₂ : C, 56.28; H, 5.97; N, 10.37; Found (%): C, 56.32; H, 5.99; N, 10.34; IR (KBr):ν3360,3150,3051,2931,2863,1724,1642,1558,1456,1255,1129,736cm ^-1 ; ¹ H-NMR(CDCl ₃ ,500MHz):δ1.22(s,3H), 1.28(s,3H),1.49(m,2H),1.60～1.95(m,4H),2.17～2.31(m,3H),2.84(m,2H),3.67(s,3H,COOCH ₃ ),5.02 (brs, 3H), 7.11 (s, 1H, H-7); ESI-MS m/z 406.1, 408.1 [M+H] ⁺ .

Example 6

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-a)

Dissolve 0.1 g of compound VII (0.25 mmol) in 15 mL of ethanol, add 0.03 g of salicylaldehyde to the mixture, stir and reflux the mixture for 10 h, a yellow solid precipitates, filter, wash with ethanol, and dry to obtain the pure compound I-a (0.04 g, 40%).

Mp241-243°C; Anal. Calcd (%) for C ₂₆ H ₂₈ BrN ₃ O ₃ : C, 61.18; H, 5.53; N, 8.23; Found (%): C, 61.20; H, 5.54; N, 8.20; IR (KBr):ν3357,2933,2342,1707,1605,1569,1474,1431,1383,1332,1254,1129,756cm ^-1 ; 1H-NMR(DMSO,300MHz):δ1.27(s,3H), 1.32(s,3H),1.54-1.62(m,2H),1.78(m,4H),1.93(m,1H),2.32(d,J＝12.5Hz,1H),2.91(m,1H),3.07 -3.16(m,1H),3.28-3.32(m,1H),3.70(s,3H),6.99(t,J=7.6Hz,1H),7.03(d,J=7.9Hz,1H),7.38( s,1H),7.44(t,J=7.5Hz,1H),7.53(d,J=6.8Hz,1H),9.42(s,1H),9.64(s,1H),12.29(s,1H); ESI-MS m/z 510.1, 512.1 [M+H] ⁺ .

Example 7

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-b)

Referring to Example 6, using 5-fluorosalicylaldehyde and compound VII as raw materials, reacted for 10 h under the same conditions, a yellow solid precipitated, filtered, washed with ethanol, and dried to obtain pure compound I-b (0.05 g, 50%).

Mp282-284°C; Anal. Calcd (%) for C ₂₆ H ₂₇ BrFN ₃ O ₃ : C, 59.10; H, 5.15; N, 7.95; Found (%): C, 59.21; H, 5.10; N, 8.02; IR (KBr):ν3419,2930,2342,1705,1614,1575,1485,1429,1330,1248,1129,858cm ^-1 ; ¹ H-NMR(DMSO,300MHz):δ1.21(s,3H),1.24 (s,3H),1.43(m,2H),1.69(m,4H),1.86(m,1H),2.13(d,J=12.0Hz,1H),2.37(d,J=12.7Hz,1H) ,2.81(m,1H),3.00(m,1H),3.64(s,3H),7.05(d,J=8.9Hz,1H),7.32(s,1H),7.34(d,J=11.1Hz, 1H), 7.76 (d, J = 6.0 Hz, 1H), 9.63 (s, 1H), 11.75 (s, 1H), 12.93 (s, 1H); ESI-MS m/z 528.1, 530.1 [M+H] ⁺ .

Example 8

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-c)

Referring to Example 6, using 5-Cl salicylaldehyde and compound VII as raw materials, reacted for 10 h under the same conditions, a yellow solid was precipitated, filtered, washed with ethanol, and dried to obtain pure compound I-c (0.048 g, 48%).

Mp257-259°C; Anal. Calcd (%) for C ₂₆ H ₂₇ BrClN ₃ O ₃ : C, 57.31; H, 4.99; N, 7.71; Found (%): C, 57.21; H, 5.10; N, 7.83; IR (KBr):ν3313,2928,2362,1707,1606,1565,1473,1378,1332,1261,1129,1031,801cm ^-1 ; ¹ H-NMR(DMSO,300MHz):δ1.21(s,3H) ,1.24(s,3H),1.37-1.47(m,2H),1.67(m,4H),1.84-1.91(m,1H),2.14(d,J＝11.5Hz,1H),2.36(d,J =14.0Hz,1H),2.73-2.86(m,1H),2.96-3.04(m,1H),3.64(s,3H),7.06(d,J=8.8Hz,1H),7.32(s,1H) ,7.61(dd,J=8.9Hz,2.7Hz,1H),8.01(d,J=2.7Hz,1H),9.62(s,1H),11.99(s,1H),12.93(s,1H); -MSm/z 542.1,546.1[M+H] ⁺ .

Example 9

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-d)

Referring to Example 6, using 5-Br salicylaldehyde and compound VII as raw materials, reacted for 10 h under the same conditions, a yellow solid precipitated, filtered, washed with ethanol, and dried to obtain pure compound I-d (0.055 g, 55%).

Mp209-212°C; Anal. Calcd (%) for C ₂₆ H ₂₇ Br ₂ N ₃ O ₃ : C, 52.99; H, 4.62; N, 7.13; Found (%): C, 52.78; H, 4.83; N, 7.07 ; IR (KBr): ν3213, 2924, 2366, 1726, 1605, 1562, 1470, 1398, 1312, 1253, 1129, 1098, 819cm ^-1 ; ¹ H-NMR (DMSO, 300MHz): δ1.21(s, 3H),1.24(s,3H),1.37-1.47(m,2H),1.69(m,4H),1.86(m,1H),2.14(d,J＝12.2Hz,1H),2.37(d,J =12.2Hz,1H),2.72-2.84(m,1H),2.95-3.03(m,1H),3.64(s,3H),7.00(d,J=8.9Hz,1H),7.31(s,1H) ,7.61(dd,J=8.6HZ,2.2Hz,1H),8.13(d,J=2.1Hz,1H),9.61(s,1H),11.98(s,1H),12.92(s,1H); -MSm/z 587.1,591.0[M+H] ⁺ .

Example 10

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-e)

Referring to Embodiment 6, using ₅ -CH salicylaldehyde and compound VII as raw materials, reacted for 10h under the same conditions, a yellow solid was precipitated, filtered, washed with ethanol, and dried to obtain pure compound Id (0.067g, 68%) .

Mp181-183°C; Anal. Calcd (%) for C ₂₇ H ₃₀ BrN ₃ O ₃ : C, 61.83; H, 5.77; N, 8.01; Found (%): C, 61.74; H, 5.88; N, 7.93; IR (KBr):ν3357,2929,2354,1719,1606,1576,1484,1380,1331,1248,1129,1034,849cm ^-1 ; ¹ H-NMR(DMSO,300MHz):δ1.21(s,3H) ,1.24(s,3H),1.37-1.47(m,2H),1.62-1.72(m,4H),1.84-1.88(m,1H),2.14(d,J=11.7Hz,1H),2.36(d ,J=12.5Hz,1H),2.72-2.81(m,1H),2.96-3.03(m,1H),3.64(s,3H),6.93(d,J=8.4Hz,1H),7.30(s, 1H), 7.31(d, J=4.9Hz, 1H), 7.72(s, 1H), 9.58(s, 1H), 11.98(s, 1H), 12.92(s, 1H); ESI-MSm/z522.2, 524.2 [M+H] ⁺ .

Example 11

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-f)

Referring to Embodiment 6, using ₅ -NO Salicylaldehyde and compound VII as raw materials, reacted for 10h under the same conditions, a yellow solid was precipitated, filtered, washed with ethanol, and dried to obtain pure compound If (0.047g, 46%) .

Mp318-320°C; Anal. Calcd (%) for C ₂₆ H ₂₇ BrN ₄ O ₅ : C, 56.22; H, 4.90; N, 10.09; Found (%): C, 56.15; H, 4.88; N, 9.98; IR (KBr): ν3297, 2928, 1759, 1608, 1573, 1477, 1342, 1287, 1260, 1130, 1109, 784cm ^-1 ; ¹ H-NMR (DMSO, 300MHz): δ1.21(s, 3H), 1.24 (s,3H),1.42(m,2H),1.65-1.69(m,4H),1.80-1.86(m,1H),2.14(d,J=12.1Hz,1H),2.37(d,J=12.2 HZ,1H),2.82(m,1H),2.98(m,1H),3.64(s,3H),7.20(d,J＝9.1Hz,1H),7.32(s,1H),8.31(d,J =8.9Hz, 1H), 8.92(s, 1H), 9.74(s, 1H), 12.79(s, 1H), 13.01(s, 1H); ESI-MS m/z 554.1, 556.1 [M+H] ⁺ .

Example 12

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-g)

Referring to Example 6, using 4-F salicylaldehyde and compound VII as raw materials, reacted for 10 h under the same conditions, a yellow solid precipitated, filtered, washed with ethanol, and dried to obtain pure compound I-g (0.065 g, 65%).

Mp176-180°C; Anal. Calcd (%) for C ₂₆ H ₂₇ BrFN ₃ O ₃ : C, 59.10; H, 5.15; N, 7.95; Found (%): C, 59.15; H, 5.04; N, 8.01; IR (KBr):ν3365,2932,1725,1617,1576,1431,1332,1284,1284,1129,1109,979,855,798cm ^-1 ; ¹ H-NMR(DMSO,300MHz):δ1.21(s,3H), 1.24(s,3H),1.34-1.47(m,2H),1.68(m,4H),1.87(m,1H),2.14(d,J=12.2Hz,1H),2.37(d,J=12.3Hz ,1H),2.75-2.85(m,1H),3.00(m,1H),3.64(s,3H),6.88(d,J=9.6Hz,2H),7.31(s,1H),8.02(s, 1H), 9.56(s, 1H), 12.59(s, 1H), 12.88(s, 1H); ESI-MS m/z 527.1, 529.1 [M+H] ⁺ .

Example 13

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-h)

Referring to Example 6, using 3-F salicylaldehyde and compound VII as raw materials, reacted for 10 h under the same conditions, a yellow solid precipitated, filtered, washed with ethanol, and dried to obtain pure compound I-h (0.046 g, 46%).

Mp276-280°C; Anal. Calcd (%) for C ₂₆ H ₂₇ BrFN ₃ O ₃ : C, 59.10; H, 5.15; N, 7.95; Found (%): C, 59.20; H, 5.03; N, 7.98; IR (KBr): ν3303, 2930, 2363, 1702, 1606, 1580, 1462, 1386, 1248, 1131, 855, 781cm ^-1 ; ¹ H-NMR (DMSO, 300MHz): δ1.21(s, 3H), 1.24( s,3H),1.39(m,2H),1.68(m,4H),1.83(m,1H),2.14(d,J=11.9Hz,1H),2.37(d,J=12.9Hz,1H), 2.80(m,1H),3.00(m,1H),3.64(s,3H),7.01(d,J=4.6Hz,1H),7.32(s,1H),7.47(t,J=8.6Hz,1H ), 7.76 (d, J=7.68Hz, 1H), 9.66 (s, 1H), 12.38 (s, 1H), 12.97 (s, 1H); ESI-MS m/z 527.1, 529.1 [M+H] ⁺ .

Example 14

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-i)

Referring to Embodiment 6, using 3,5-dichlorosalicylaldehyde and compound VIII as raw materials, reacted for 10h under the same conditions, a yellow solid was precipitated, filtered, washed with ethanol, and dried to obtain pure compound I-i (0.057g, 57 %).

Mp295-298°C; Anal. Calcd (%) for C ₂₆ H ₂₆ BrCl ₂ N ₃ O ₃ : C, 53.90; H, 4.52; N, 7.25; Found (%): C, 53.97; H, 4.32; N, 7.54 ; IR (KBr): ν3302, 2931, 2356, 1702, 1604, 1503, 1452, 1331, 1248, 1176, 1129, 856, 729 cm ^-1 ; ¹ H-NMR (DMSO, 300MHz): δ1.21 (s, 3H ),1.24(s,3H),1.33-1.48(m,2H),1.69(m,5H),2.14(d,J＝11.9Hz,1H),2.37(d,J＝12.0Hz,1H),2.78 -2.97(m,2H),3.64(s,3H),7.34(s,1H),7.82(s,1H),8.04(s,1H),9.61(s,1H),13.05(s,1H), 13.28 (s, 1H); ESI-MS m/z 577.0, 581.0 [M+H] ⁺ .

Example 15

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-j)

Referring to Embodiment 6, using 4-diethylaminosalicylaldehyde and compound VIII as raw materials, reacted for 10h under the same conditions, a yellow solid was precipitated, filtered, washed with ethanol, and dried to obtain pure compound I-j (0.037g, 37 %).

Mp 195-197°C; Anal. Calcd (%) for C ₃₀ H ₃₇ BrN ₄ O ₃ : C, 61.96; H, 6.41; N, 9.63; Found (%): C, 61.87; H, 6.23; N, 9.84; IR (KBr): ν3386, 2925, 1725, 1636, 1583, 1469, 1347, 1259, 1131, 1097, 1033, 799 cm ^-1 ; ¹ H-NMR (DMSO, 300MHz): δ1.14 (t, J＝6.5Hz ,6H),1.20(s,3H),1.24(s,3H),1.40(m,2H),1.69(m,6H),2.13(d,J＝12.5Hz,1H),2.36(d,J＝ 11.5Hz, 1H), 2.72-2.82(m, 1H), 2.93-3.00(m, 1H), 3.44(d, J=7.0Hz, 4H), 3.64(s, 3H), 6.14(s, 1H), 6.40(d,J=8.2Hz,1H),7.23(s,1H),7.56(d,J=8.8Hz,1H),9.29(s,1H),12.48(s,1H),12.80(s,1H ); ESI-MS m/z 580.2, 582.2 [M+H] ⁺ .

Example 16

Synthesis of Dehydroabietic Acid Benzimidazole Schiff Base Heterocyclic Derivatives (I-k)

Referring to Embodiment 6, using 1-hydroxyl-2-naphthaldehyde and compound VIII as raw materials, reacted for 10h under the same conditions, a yellow solid was precipitated, filtered, washed with ethanol, and dried to obtain pure compound I-k (0.043g, 43% ).

Mp315-317°C; Anal. Calcd (%) for C ₂₉ H ₂₇ BrN ₃ O ₃ : C, 63.86; H, 4.99; N, 7.70; Found (%): C, 63.68; H, 5.03; N, 7.87; IR (KBr):ν3396,2941,1723,1623,1564,1468,1326,1252,1128,819,745cm ^-1 ; ¹ H-NMR(DMSO,300MHz):δ1.21(s,3H),1.25(s, 3H), 1.39-1.49(m, 2H), 1.63-1.70(m, 4H), 1.81-1.88(m, 1H), 2.16(d, J=11.9Hz, 1H), 2.38(d, J=12.4Hz ,1H),2.87(m,1H),3.01(m,1H),3.64(s,3H),7.25(d,J=9.0Hz,1H),7.32(s,1H),7.47(t,J= 7.3Hz, 1H), 7.68(d, J=7.6Hz, 1H), 7.93(d, J=7.9Hz, 1H), 8.10(d, J=9.0Hz, 1H), 8.56(d, J=8.0Hz ,1H), 10.26(s,1H), 12.91(s,1H), 14.35(s,1H); ESI-MS m/z 544.1,546.1[M+H] ⁺ .

Example 17

In vitro antitumor activity screening

Screening cell lines are: human liver cancer cells HepG2 and SMMC-7721.

experimental method:

Take cells in good logarithmic growth phase, digest with trypsin, and make a suspension of 5×104 cells/mL. The cell suspension was transferred into a 96-well culture plate, 100 μL per well, and cultured at 37° C. and 5% CO2 for 24 hours.

The test derivatives were prepared into a certain concentration of mother solution with DMSO, and then diluted with RPMI1640 medium to dilute the derivative mother solution into different concentration dilutions. Remove the old medium, add different concentrations of drug-containing medium, 100 μL per well. A blank control group and a positive control etoposide (VP-16) control group were also set up. After 24 hours of drug action, discard the drug-containing medium, add 100 μL of serum-free and phenol red-free 1640 medium to each well, then add 10 μL of MTT solution (5 mg/mL), and continue to incubate for 4 hours.

Aspirate the supernatant in each well, add 150 μL of DMSO to each well, and shake for 10 minutes to fully dissolve the crystals. Measure the light absorption value (OD value) of each well at 490 nm with a microplate reader, and calculate the inhibition rate of cell proliferation: Inhibition rate ( %)=(1-average OD value of medication group/average OD value of blank control group)×100%. SPSS 16.0 software was used for data processing and the half inhibitory concentration (IC50) of cancer cell proliferation was calculated. The results are shown in Table 1. Table 1 shows the in vitro proliferation inhibitory effect of dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives on Hep-G2 cells.

Table 1

As shown in Table 1, the synthesized dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives all have strong inhibitory effect on these two tumor cells, wherein compounds I-a, I-b, I-d, I-e, I-h, I-i and I-j have strong inhibitory effect on HepG2 cells, which is stronger than the positive control etoposide; while compounds I-b, I-e and I-j have strong activity on SMMC-7721 cells, which is close to the positive control etoposide. Among these compounds, I-e has the strongest antitumor activity. The above results show that these compounds have a significant inhibitory effect on liver cancer cells, and have the potential to develop anticancer drugs.

The basic principles, main features and advantages of the present invention have been shown and described above. Those skilled in the industry should understand that the present invention is not limited by the above-mentioned embodiments. What are described in the above-mentioned embodiments and the description only illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will also have For various changes and improvements, the protection scope of the present invention is defined by the appended claims, description and their equivalents.

Claims (4)

1. A dehydroabietic acid benzimidazole Schiff base heterocyclic derivative with a structure shown as a general formula I and pharmaceutically acceptable salts thereof:

wherein,

2. the method for preparing the dehydroabietic acid benzimidazole schiff base heterocyclic derivative having the structure represented by the general formula i as set forth in claim 1, which comprises the steps of:

(1) dehydroabietic acid is subjected to acyl chlorination and methyl esterification to obtain dehydroabietic acid methyl ester, which has a structure shown in a general formula III:

(2) the dehydroabietic acid methyl ester is subjected to NBS bromination to obtain 12-bromo dehydroabietic acid methyl ester, which has a structure shown in a general formula IV:

(3) the 12-bromo-dehydroabietic acid methyl ester is subjected to fuming nitric acid double nitration to obtain 12-bromo-13, 14-dinitro de-isopropyl dehydromethyl ester, which has a structure shown in a general formula V:

(4) reducing the 12-bromo-13, 14-dinitrodeisopropyldehydromethyl ester by Fe/HCl to obtain 12-bromo-13, 14-diamino deisopropyldehydroabietic acid methyl ester, which has a structure shown in a general formula VI:

(5) the 12-bromine-13, 14-diamino isopropyl-removed dehydroabietic acid methyl ester reacts with cyanogen bromide to prepare the dehydroabietic acid imidazole derivative, which has a structure shown in a general formula VII:

(6) the dehydroabietic acid imidazole derivative reacts with salicylaldehyde with different substituents to prepare a dehydroabietic acid Schiff base derivative with corresponding substituents, and the derivative has a structure shown in a general formula I:

wherein,

3. the use of the dehydroabietic acid benzimidazole schiff base heterocyclic derivative having the structure shown in formula I and the pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a medicament for treating tumors.

4. Use according to claim 3, characterized in that: the tumor is liver cancer.